Transgenic Mice Expressing CNO-sensitive Gq- or Gs-coupled Designer Receptors Selectively in Pancreatic Beta Cells


Impaired functioning of pancreatic beta cells is a key hallmark of type 2 diabetes. Beta cell function is modulated by the actions of different classes of heterotrimeric G proteins. The functional consequences of activating specific beta cell G protein signaling pathways in vivo are not well understood at present, primarily due to the fact that beta cell G protein-coupled receptors (GPCRs) are also expressed by many other tissues. To circumvent these difficulties, we developed a strategy that allows for the conditional and selective activation of specific beta cell G proteins in intact animals. Specifically, we created two lines of transgenic mice each of which expressed a specific designer GPCR (DREADD = Designer Receptor Exclusively Activated by a Designer Drug) in beta cells only (beta-RASSL-1 = RIPII-Rq Tg = beta Gq DREADD transgenic mice; beta-RASSL-2 = RIPII-Rs = beta Gs DREADD transgenic mice). Importantly, the two designer receptors differ in their G protein-coupling properties (Gq versus Gs). They are unable to bind endogenous ligand(s), but can be efficiently activated by an otherwise pharmacologically inert compound (clozapine-N-oxide = CNO), leading to the conditional activation of either beta cell Gq or Gs G proteins. These newly developed transgenic mice represent powerful new tools to study G protein regulation of beta cell function in vivo.

Potential Commercial Applications: Competitive Advantages:
  • Probing beta cell signalling pathways.
  • Drug design and development.
 
  • Simplified study of pathways in single cell type, beta cells, in vivo.


Inventors:

Jurgen Wess (NIDDK)  ➽ more inventions...

Jean-Marc Guettier (NIDDK)  ➽ more inventions...


Intellectual Property:
Research Tool – Patent protection is not being pursued for this technology.

Publications:
Guettier JM et al. A chemical-genetic approach to study G protein regulation of Beta-cell function in vivo. Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19197-202. PMID: 19858481

Collaboration Opportunity:

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is seeking statements of interest from parties interested in collaborative research to further evaluate signalling pathways in beta cells. For collaboration opportunities, please contact: Marguerite J. Miller at Marguerite.Miller@nih.gov or 301-496-9003.


Licensing Contact:
Mythreyi Shastri, Ph.D.
Email: shastrim@mail.nih.gov
Phone: 301-435-0613

OTT Reference No: E-197-2016-0
Updated: Apr 17, 2017